Previous attempts to obtain high-fidelity tracings from the point of maximal pulse of the heart beat—referred as apexcardiography—have been handicapped mainly because of lack of an advanced instrumentation and automated evaluation of exactly defined diastolic indices as well as of exactly defined patterns, types and forms of isometric exercise-induced changes in diastolic profile.
Pressocardiography represents the only noninvasive technique which is obtained by means of an external pressure transducer transthoracically, providing the opportunity to measure LV pressure curve changes in diastole at rest and during short isometric exercise (called Handgrip-pressocardiographic test=HAT) by an operator with minimal medical skills.
This diastolic stress test HAT presents the opportunity to measure diastolic performance of the human left ventricle and detect life-threatening abnormal heart conditions in an early phase before development of symptoms or ECG or other signs of myocardial disease states and especially coronary artery disease.
Conclusive evidence exists based predominantly in comparison of simultaneously recorder pressocardiographic and LV pressure curves during heart catheterization that the former mirrors in time and slope the latter. It is widely accepted that invasively obtained LV pressure curves by means of micromanometer represent still today the gold standard for examining the accuracy of diastolic function assessment. The most common diastolic indices which are assessed by means of such high-fidelity LV pressure recordings are the calculation of LV pressure fall (=relaxation) variables, like time constant of relaxation (Tau) and the total LV relaxation time, and end-diastolic variables, like LV end-diastolic pressure, pre-atrial or pre-A wave as well as peak atrial pressures.
On the other hand, current methods of measuring diastolic LV function are either extremely invasive or/and costly or/and noninvasively imaging approaches that require expertise and time-consuming measurements by highly skilled operators. Examples of the former invasive techniques are left and right heart catheterization with subsequent angiographic evaluation (coronary angiography and ventriculography) as well as nuclear ventriculography. An example of the latter are all Doppler echocardiographic techniques providing ultrasonic dynamic images of the heart like transmitral flow velocities, pulmonary venous flow assessment, acoustic quantification, flow propagation assessment and the most recently introduced Tissue Doppler Imaging (TDI) and Strain-Rate Imaging (SRI); however, all these Doppler techniques require highly and expensively developed laboratories as well as skilled interpretation, whereas in most cases there is a lack of exact definition of normal limits and/or of standardization.
Consequently, there was hitherto a lack to assess LV diastolic function alterations, accurately as well as noninvasively, rapidly and safely; and above no simple and at best portable instrumentation—at best in pocket size—using an external pressure transducer with infinite time constant.
In contrast, with the present invention using the diastolic exercise test by means of handgrip-pressocardiography and a portable—at best pocket-sized—instrument, a rapid estimation of diastolic LV function can be performed quickly and noninvasively everywhere, i.e. at every office, at outpatient clinic (incl. CPUs) and even at patient's home, with no requirement of skilled interpretation both at rest and during isometric exercise. A simple readout can provide exact information about early and late diastolic abnormalities within few minutes.
It has been shown using micromanometer measurements and internal LV pressure recordings that the changes of some diastolic variables during isometric handgrip exercise, especially at the end-diastole, is rather characteristic for the presence of some myocardial disease states. Whereas patients with normal or nearly normal LV function show no or only minimal diastolic changes during isometric exercise, patients with coronary artery disease show mostly dramatic alterations and particularly rise in LV end-diastolic pressure. It should be noted that this rapidly occurring and high elevation of LV end-diastolic pressure is also present during other exercise modalities like dynamic exercise by means of bicycle or treadmill.
The inventor has found for the first time that a very similar dramatic changes in early and/or late diastole during isometric exercise occur also using the handgrip-pressocardiography technique in patients with known or subsequently proved coronary artery disease, whereas healthy subjects show no or minimal changes within exactly defined normal limits. Thus, it appears that changes in pressocardiographic curve are also during handgrip exercise unidirectional and similar to those found internally in LV pressure curve during catheterization; the former corresponding the latter.
It was realized by the inventor for the first time that these significant diastolic alterations during exercise-induced ischemia represent a characteristic sign which was called an “ischemic diastolic response” of pressure tracings recorded either invasively or noninvasively. It should be also noted that the corresponding volumetric measurements are less dramatic having a minor magnitude.
The diagnosis of coronary artery disease or other myocardial diseases based on symptoms is not accurate enough, since these symptoms occur rather late in the course of most myocardial diseases and atypical and above not infrequently entirely absent. Alternatively, ECG and systolic abnormalities are usually preceding the onset of symptoms; whereas diastolic dysfunction represents the earliest manifestation in the course of most myocardial diseases.
Conclusive evidence exists that the earliest manifestation of ischemia is diastolic dysfunction—relaxation and end-diastolic abnormalities, preceding both the ECG and the systolic abnormalities on the onset of every ischemic episode. It has been proved in human beings that during ischemia induced by occlusion of a coronary vessel during angioplasty in the left anterior coronary vessel, an extreme prolongation of total relaxation time of the left ventricle occurs within few seconds and is followed after 15–25 sec by a dramatic rise in LV end-diastolic and left atrial pressures which are reaching a more than 150% of the base line values.
Based on heart catheterization data and high-fidelity LV pressure curve using micromanometers and exact early (relaxation) and late (end-diastolic and left atrial pressures) measurements, it has further been shown that diastolic abnormalities as assessed by LV pressure curve measurements are much more pronounced than volumetric abnormalities in diastole or systole (including left ventricular ejection fraction).
Therefore, it appears that the assessment of LV pressure curve in diastolic phase in everyday practice at rest and during short exercise could be of fundamental clinical importance. Further, it is also logical to assume that an instrumentation assessing these early occurring latent exercise-inducible diastolic abnormalities, could represent a very useful diagnostic tool for an early detection of LV dysfunction due to ischemic or other myocardial diseases.
Further, it is also expected that the application of a simple small and user friendly device—at best portable and in pocket size—for obtaining a “diastolic stress test” assessing the mentioned early and late LV pressure curve changes in everyday practice, would be a very useful daily tool leading us probably to an earlier identification of patients with subclinic CAD before the onset of symptoms or systolic dysfunction (assessed by echocardiogram) or electrical changes (in ECG).
The wide application of such instrumentation would probably result in an improved secondary prevention since it would lead us to an earlier onset of preventive and/or therapeutic strategies.
Most importantly, an isometric handgrip exercise of 2 min duration represents a low level stress to the human left ventricle and all alterations are quickly reversible. In addition, this quick and slight handgrip exercise can be performed on the bed using the one hand. Consequently, this stress test can be widely applied, independently from physical ability, age and health state; i.e. also in disabled and extreme obese persons.
Before the introduction of handgrip-pressocardiography, there was no other simple (needing no expertise and skilled interpretation), noninvasive, quick (procedure of <10 min duration) and safe (no serious complications including myocardial infarction and deaths) as well convenient for all patients diagnostic modality suitable to be applied as screening test for myocardial diseases—including coronary artery disease—even in the earliest subclinic stage.
The probably greatest problem in cardiology but also in health care is still the early identification of subclinic myocardial diseases and especially of asymptomatic patients with coronary artery disease.
Most practitioners are still based on the daily application of resting ECG or stress ECG or resting Echocardiography neither of which is sensitive enough for myocardial disease detection—especially in the earliest asymptomatic stage. Alternatively, more sensitive and specific methods such as nuclear (Thallium) imaging or stress echocardiography (including transeosophageal echo) are time-consuming, not completely non-invasive, very costly and require expert interpretation. Further, dynamic exercise or pharmacological stress tests are not convenient and not completely safe for the patients; resulting either to a decreased desire of the patients or even contraindication for performing them. Therefore, these techniques can not be applied very widely and above they are rather excluded for use by primary care physicians.
This lack of appropriate, accurate and easy applicable techniques for screening healthy looking and feeling patients for “silent myocardial disease states, results in a great still unsolved problem in health care; namely, there are still today yearly >220.000 patients in US dying suddenly due to silent myocardial disease remaining mostly unidentified prior to their sudden death. The underlying disease was in >70% of these cases asymptomatic coronary artery disease and in younger population in >30% undiagnosed “silent” cardiomyopathies.
It should also be emphasized that usually healthy feeling and looking patients in early and sometimes even more advanced stages of myocardial disease, are not coming to the great or university hospitals or at the office of cardiologists in order to be examined by means of the mentioned more sophisticated diagnostic techniques. Thus, these asymptomatic patients suffering on subclinic myocardial disease could only being diagnosed by primary care physicians who, however, do not have enough diagnostic tools for such a screening. In this context, it should be again noted that electrical (resting and stress ECG) and anatomic changes as well as systolic abnormalities (in resting echocardiogram) are all occurring mostly much later in the course of myocardial disease.
A wider application of diastolic tools as diagnostic modalities of early myocardial function alterations appear to represent an alternative useful approach. The classical diastolic tools which are widely accepted for detecting LV diastolic dysfunction are Doppler-echocardiographic and nuclear techniques as well as more recently magnetic resonance imaging techniques. All of them have one or more of the following limitations: they are time-consuming, costly, not standardized and require expert interpretation. Thus, they can not be applied by primary care physicians. In addition, although the gold standard of assessing LV diastolic function are still the internally derived LV pressure curve measurements, all of the mentioned current diastolic techniques are assessing the volumetric filling profile—and this only at rest—and none is using a pressure transducer.
Because of all these limitations and disadvantages, one should conclude that although there is no doubt about the existing and significantly increasing interest on and the clinical importance of diastolic function assessment, the clinical application of diastolic techniques in the daily practice remains rather limited.
In contrast, a HAT detection of subclinic myocardial disease can be accomplished easily, quickly, safely and conveniently with a high sensitivity and specificity in almost every patient and with a simple read out rather than expert interpretation, with the present invention. Most importantly, this diastolic stress test can be performed everywhere by a portable or even pocket sized instrument.
Previous attempts at obtaining and evaluating (apex)pressocardiographic waveforms have been handicapped by the lack of advanced instrumentation, signal processing and pattern recognition techniques. The pulse transducers which have been used had a mostly unknown or too low time constant (<3 sec) using an AC input and piezoelectric recording systems with air transmission by means of air filled tubes. Moreover, they were obtained only at rest and/or after dynamic exercise, whereas the diastolic waves could not be exactly evaluated due to too high heart rate. Both amplitude and above relaxation time indices are greatly influenced by the mode of pick up device and time constant of the pressure transducer. In past years, air-filled tubes were used for transmission of the pulse signal and transducers with too short time constant resulting in distorted tracings.
These earliest versions of “displacement cardiography” were designed as ballistocardiography and kinetocardiography being rather qualitatively than quantitatively evaluated and mostly also in relation to the phonocardiographic recordings. All these tracings as well as carotid pulse and jugular vein recordings have been used for many years in the daily practice as routine tools being termed mechanocardiography. Out of all these earlier developments only arterial pulse recordings have survived which have began recently to be reevaluated as “arterial pulse wave” tracings for evaluating arterial pulse wave velocity and arterial elasticity or compliance, which is again receiving widespread acceptance.
The (apex)cardiography has been primarily used for an improved interpretation of heart sound and murmurs. However, already in earlier years the significance of measuring the relative A wave amplitude and less also of the relaxation time of the “apex tracing”. Using for the first time simultaneously external and internal pressure transducers with infinite time constant for obtaining high-fidelity tracings during heart catheterization, Jan Manolas and other cardiologists in University of Zurich, proved for the first time in human beings the significant correlation between relative A wave indices and total Relaxation time indices of the external pressure curves with the corresponding LV end-diastolic pressure and relaxation speed indices derived internally from the LV pressure curve (Ref. 3).
The Handgrip-pressocardiographic Test (HAT) has been introduced and first published in 1990 and further developed till today by Dr. Jan Manolas. The present inventor has recognized that the technology for clinical application requires an exact definition of normal limits of the diastolic indices of LV function and a positive-negative diagnosis of the presence of myocardial dysfunction and underlying myocardial disease as well as an assessment of the severity of this functional abnormality. Additionally, the inventor also recognized that by introducing an exact definition of the profile of handgrip-induced changes of the diastolic variables, one can easily discriminate among different diastolic behavior patterns.
The aim of this diastolic stress test is to assess the level of some diastolic variables corresponding to analogous diastolic function indices derived from left ventricular (LV) pressure curve as well as changes of these parameters with exercise, exploring its usefulness as an initial screening tool in identifying patients with LV diseases including coronary artery disease.
The HAT technique is obtained by a pressure transducer and mirrors LV pressure curve in time and slope; however, in contrast to the latter it is obtained noninvasively. This stress pressocardiography can be applied safely and in a convenient way in every patient, since it is of short duration and the exercise mode is only a low level isometric handgrip performed by the one hand with the patient being recumbent on the bed. Therefore, this low level stress test can be widely applied, independently from the level of physical ability, age and health state of the patient.
Before the introduction of HAT, there was no other noninvasive, simple (not needing expertise), quick (of <10 min duration), safe (without potential life threatening complications like acute infarction, ventricular tachycardia or deaths), and convenient for the patient and examinator for diagnosing myocardial diseases, including coronary artery disease.
A similar device is for obtaining a HAT is partly reported by DE 197 40 931 C2. This device consists in an external pressure transducer for obtaining noninvasive pressure curves and a balloon dynamometer for allowing the patient to perform an isometric handgrip exercise and a device for calculating diastolic parameters derived from the pressocardiographic curve at rest and during handgrip exercise in order to receive some diagnostic information about the presence or not of early and late diastolic abnormalities.
However, the received information needs a skilled further interpretation by a cardiologist and does not allow a rapid automated cardiac performance and diastolic behavior estimation by every non-expert physician or lab assistant, since an information about differentiation of underlying disease (ischemia vs non-ischemic or hypertensive myocardial disease vs Cardiomyopathy etc.) could not be derived from this previous technology.
As previously described, a device for isometric handgrip exercise by the patient is used, e.g a balloon dynamometer, which should be squeezed at approximately 40% of the maximal voluntary contraction during 2 min. At rest during and after handgrip exercise the following variables are calculated semi-automatically by means of a normalized pressocardiographic and phonocardiographic digital signal:                A/H=the relative A wave height to total systolic-diastolic excursion of pressocardiogram        A/D=the relative A wave to total diastolic height of pressocardiogram        TART=the Total (Apex)pressocardiographic Time from begin of aortic component of the second heart sound to the protodiastolic nadir of pressocardiographic curve or O point.        TARTI=the Total (Apex)pressocardiographic Relaxation Time Index, which is given by the following formula:TARTI=√{square root over (A2−C)}/TARTwhere A2 is the onset of the aortic component of the second heart sound in the phonocardiogram and C the onset of the pressocardiographic systolic upstroke. TARTI represents a modified Bazett formula, which has been used to correct temporal variables for heart rate; whereas the duration of diastolic phase is being used instead of R-R interval.        DATI=the Diastolic Amplitude Time Index, which represents the first attempt to assess by a combined single index the total early and late diastolic function and is given by the following formula:DATI=TARTI/(A/D)        
Based on the absolute value of these diastolic indices at rest and during exercise, one can receive some diagnostic information. The presence of diastolic dysfunction is estimated by evaluation of a “positive” test result. Further, the presence of early or/and late diastolic abnormalities was evaluated for defining some types of diastolic dysfunction during handgrip exercise. This approach has, however, some significant shortcomings:                1. The mentioned definition of positive/negative and of diastolic types was based on normal limits according to published papers of the present inventor, which were obtained by a transducer having a different time constant from the mentioned new device.        2. Patients without or only borderline myocardial dysfunction showed a “false positive” test result and the definition of different types was incomplete.        3. No exactly defined classification of the severity of LV diastolic dysfunction and myocardial disease could be provided        4. No exactly defined differentiation of underlying myocardial disease with automatic classification of these patients could be provided        5. A positive HAT result & types definition could not help us significantly in decision making (to be admitted or discharged) in cases of atypical unstable angina        6. A positive HAT result & types could not help us greatly in decision about performing a coronary angiography.        
This patent application addresses these previous shortcomings and difficulties in automated interpretation of HAT for improving the interpretation and diagnostic power and practically usefulness of this “diastolic stress test” as initial screening tool by providing an improved appropriate device which allows a more rapid automated diastolic performance estimation and myocardial ischemia in a robust manner without the need of physician or other expert interpretation.
The present inventor recognized that the by him introduced HAT technology requires some methodical and instrumental improvements.
A new definition of the positive/negative result and evaluation of types and a revised formulation of exactly defined diastolic patterns & an introduction of diastolic differentialforms for distinguishing between ischemic vs non-ischemic handgrip-induced alterations and hypertensive vs cardiomyopathic vs coronary vs congestive vs advanced, respectively.
The automated interpretation by a portable and at best pocket sized instrument, avoids the necessity of visual and empirical interpretation of the test result by experts, whereas its small size is further enhancing considerably the practical clinical applicability of this simple stress test.
The inventor has recognized that the present state of the art showed some significant limitations preventing a widespread clinical application especially on the level of primary care. There was a limited automated evaluation of the result and above a non-existent separation of patients with various myocardial diseases based on exactly defined patterns and forms of LV diastolic behavior.
Since primary care physicians still do not have any simple and cost-effective diagnostic techniques which could be used as initial screening tools for early identifying and differentiating patients with suspected or unknown subclinic myocardial diseases—including coronary artery disease, there is a continuing intense interest in introducing simple methods and appropriate instrumentation for quick and safe cardiac evaluation by non-experts in daily practice for preventing acute myocardial infarction or sudden death.